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Frontiers in Immunology 2023Transfusion-dependent non-severe aplastic anemia (TD-NSAA) is a rare condition of bone marrow failure that can persist for a long time or develop into severe aplastic...
Transfusion-dependent non-severe aplastic anemia (TD-NSAA) is a rare condition of bone marrow failure that can persist for a long time or develop into severe aplastic anemia (SAA). Little is known about the clinical and laboratory characteristics, and disease prognosis and outcomes in TD-NSAA patients. The clinical and laboratory data of 124 consecutive TD-NSAA patients in the Chinese Eastern Collaboration Group of Anemia from December 2013 and January 2017 were analyzed retrospectively. In 124 TD-NSAA patients, the median age was 32 years (range: 3-80) and the median disease course was 38 months (range: 3-363). Common complications were iron overload (53/101, 52.5%), liver and kidney dysfunction (42/124, 33.9%), diabetes mellitus/impaired glucose tolerance (24/124, 19.4%), and severe infection (29 cases, 23.4%). 58% of patients (57/124) developed severe aplastic anemia with a median progression time of 24 months (range: 3-216). Patients with absolute neutrophil count (ANC) <0.5×10/L, severe infection, or iron overload had a higher probability of progression to SAA (P=0.022, P=0.025, P=0.001). Patients receiving antithymocyte globulin (ATG) plus Cyclosporin A (CsA) had a higher overall response rate compared to those receiving CsA alone (56.7% vs 19.3%, P < 0.001). The addition of ATG was the favorable factor for efficacy (P=0.003). Fourteen patients developed secondary clonal hematologic disease: eleven patients with paroxysmal nocturnal hemoglobinuria, two patients with myelodysplastic syndromes, and one patient with acute myeloid leukemia, respectively. Ten patients (8.1%) died with a median follow-up of 12 months (range: 3- 36 months). Patients with TD-NSAA usually have a prolonged course of disease, and are prone to be complicated with important organ damage and disease progression to SAA. Intensive immunosuppressive therapy based on ATG might be an appropriate approach for TD-NSAA. http://www.chictr.org.cn/edit.aspx?pid=125480&htm=4, identifier ChiCTR2100045895.
Topics: Humans; Adult; Anemia, Aplastic; Retrospective Studies; Cyclosporine; Antilymphocyte Serum; Iron Overload
PubMed: 37497227
DOI: 10.3389/fimmu.2023.1197982 -
Haematologica Jun 2019
Topics: Antilymphocyte Serum; Graft Rejection; Hematopoietic Stem Cell Transplantation; Humans; Myelodysplastic Syndromes; Neoplasms; Transplantation Conditioning; Whole-Body Irradiation
PubMed: 31152088
DOI: 10.3324/haematol.2019.216952 -
[Rinsho Ketsueki] the Japanese Journal... 2021Treatments of aplastic anemia comprise supportive therapy and aplastic anemia-specific therapy to recover from hematopoiesis. Supportive therapy includes transfusion,...
Treatments of aplastic anemia comprise supportive therapy and aplastic anemia-specific therapy to recover from hematopoiesis. Supportive therapy includes transfusion, granulocyte colony-stimulating factor, and iron chelation therapy in addition to symptomatic treatment. Aplastic anemia-specific treatments that aim to achieve hematopoietic recovery are immunosuppressive therapy, thrombopoietin receptor agonist (TPO-RA) treatment, allogeneic hematopoietic stem cell transplantation, and anabolic hormone therapy. Although the transplantation achieves complete recovery of hematopoiesis (healing), there is a risk of death from transplant-related complications. The most effective drug therapy is the combination of TPO-RA and the immunotherapy combined with anti-thymocyte globulin and cyclosporine. This treatment is also effective against secondary, drug-induced, or hepatitis-associated aplastic anemia. In the treatment of aplastic anemia, the treatment choice is made based on the disease severity and patient ages.
Topics: Anemia, Aplastic; Antilymphocyte Serum; Cyclosporine; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Humans
PubMed: 34497232
DOI: 10.11406/rinketsu.62.922 -
Internal Medicine Journal Feb 2019Acquired aplastic anaemia is a rare, serious, immunologically mediated bone marrow failure syndrome, characterised by marrow hypoplasia of varying severity and... (Review)
Review
Acquired aplastic anaemia is a rare, serious, immunologically mediated bone marrow failure syndrome, characterised by marrow hypoplasia of varying severity and significant pancytopenia. Careful attention and investigation, including molecular testing, is required to confirm the diagnosis and exclude other mimicking conditions, such as inherited bone marrow failure syndromes. In a proportion of patients, the disease evolves to myelodysplasia or acute myeloid leukaemia and in some there is an association with paroxysmal nocturnal haemoglobinuria. The disease has a major impact on patient quality of life. Haemopoietic stem/progenitor cell transplantation for eligible patients with an available donor is the only current curative therapy. Other patients may receive immunosuppression, most commonly with anti-thymocyte globulin and cyclosporin. An initial response to immunosuppression is often encouraging, but relapse is common. Supportive care, including management of transfusion requirements and infections, is central to management. Promising new diagnostic tools and emerging therapies will likely transform approaches to this important, chronic and life-threatening condition.
Topics: Anemia, Aplastic; Antilymphocyte Serum; Blood Transfusion; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Pancytopenia; Recurrence
PubMed: 30324755
DOI: 10.1111/imj.14140 -
Frontiers in Immunology 2022Vascularized bone marrow (VBM) is essential in tolerance induction through chimerism. We hypothesized that the inclusion of VBM contributes to the induction of mystacial...
INTRODUCTION
Vascularized bone marrow (VBM) is essential in tolerance induction through chimerism. We hypothesized that the inclusion of VBM contributes to the induction of mystacial pad allotransplantation tolerance.
METHOD
In this study, 19 VBM, nine mystacial pad, and six sequential VBM and mystacial pad allografts were transplanted from Brown Norway (BN) rats to Lewis (LEW) rats to test our hypothesis. The VBM recipients were divided into antilymphocyte serum (ALS) monotherapy group (two doses of ALS on day 3 pretransplantation and day 1 posttransplantation), immunosuppressant group [a week of 2 mg/kg/day tacrolimus (Tac) and 3 weeks of 3 mg/kg/day rapamycin (RPM)], and combined therapy group. The mystacial pad recipients were divided into VBM and non-VBM transplantation groups, and both groups were treated with an immunosuppression regimen that consists of ALS, Tac, and RPM. For the recipients of sequential VBM and mystacial pad allotransplantations, additional Tac was given 1 week after mystacial pad transplantation. Allograft survival, donor-specific tolerance, and chimerism level were evaluated.
RESULTS
With the administration of ALS and short-term Tac and RPM treatments, VBM recipients demonstrated long-term graft survival (>120 days) with persistent chimerism for 30 days. CD3 T cells from tolerant rats showed donor-specific hyporesponsiveness and tolerance to donor skin grafts but not to third-party counterparts. Furthermore, mystacial pad graft recipients with VBM transplantation exhibited a higher allograft survival rate than those without VBM transplantation [median survival time (MST) >90 days vs. 70 days, < 0.05].
CONCLUSION
This study demonstrated that VBM transplantation is an efficient strategy to induce and maintain donor-specific tolerance for an osseous-free allograft.
Topics: Animals; Rats; Antilymphocyte Serum; Bone Marrow; Graft Rejection; Rats, Inbred BN; Rats, Inbred Lew; Sirolimus; Tacrolimus; Transplantation Tolerance
PubMed: 36578498
DOI: 10.3389/fimmu.2022.1059271 -
Clinical Pharmacokinetics May 2016Part I of this article included a pertinent review of allogeneic hematopoietic cell transplantation (alloHCT), the role of postgraft immunosuppression in alloHCT, and... (Review)
Review
Part I of this article included a pertinent review of allogeneic hematopoietic cell transplantation (alloHCT), the role of postgraft immunosuppression in alloHCT, and the pharmacokinetics, pharmacodynamics, and pharmacogenomics of the calcineurin inhibitors and methotrexate. In this article (Part II), we review the pharmacokinetics, pharmacodynamics, and pharmacogenomics of mycophenolic acid (MPA), sirolimus, and the antithymocyte globulins (ATG). We then discuss target concentration intervention (TCI) of these postgraft immunosuppressants in alloHCT patients, with a focus on current evidence for TCI and on how TCI may improve clinical management in these patients. Currently, TCI using trough concentrations is conducted for sirolimus in alloHCT patients. Several studies demonstrate that MPA plasma exposure is associated with clinical outcomes, with an increasing number of alloHCT patients needing TCI of MPA. Compared with MPA, there are fewer pharmacokinetic/dynamic studies of rabbit ATG and horse ATG in alloHCT patients. Future pharmacokinetic/dynamic research of postgraft immunosuppressants should include '-omics'-based tools: pharmacogenomics may be used to gain an improved understanding of the covariates influencing pharmacokinetics as well as proteomics and metabolomics as novel methods to elucidate pharmacodynamic responses.
Topics: Animals; Antilymphocyte Serum; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Mycophenolic Acid; Pharmacogenetics; Sirolimus
PubMed: 26620047
DOI: 10.1007/s40262-015-0340-9 -
Clinical Nephrology Aug 2023Atypical hemolytic uremic syndrome (aHUS) is a genetic-based thrombotic microangiopathy (TMA) that is mediated by the activation of the alternative complement pathway....
PURPOSE
Atypical hemolytic uremic syndrome (aHUS) is a genetic-based thrombotic microangiopathy (TMA) that is mediated by the activation of the alternative complement pathway. Heterozygous deletion in CFHR3-CFHR1 occurs in 30% of the general population and has not been classically linked to aHUS. Post-transplant aHUS has been associated with a high rate of graft loss. Herein, we report our case series of patients who developed aHUS after solid-organ transplantation.
MATERIALS AND METHODS
Five consecutive cases of post-transplant aHUS were identified at our center. Genetic testing was performed in all but one.
RESULTS
One patient had a presumed TMA diagnosis before transplant. One heart and 4 kidney (KTx) transplant recipients were diagnosed with aHUS based on the clinical picture of TMA, acute kidney injury, and normal ADAMTS13 activity. Genetic mutation testing revealed heterozygous deletion in CFHR3-CFHR1 in 2 patients and a heterozygous complement factor I (CFI) variant of uncertain clinical significance (VUCS) (Ile416Leu) in a third. Four patients were on tacrolimus, 1 had anti-HLA-A68 donor-specific antibody (DSA), and another had borderline acute cellular rejection at the time of aHUS diagnosis. Four responded to eculizumab, and 1 out of 2 patients came off renal replacement therapy. One KTx recipient died from severe bowel necrosis in the setting of early post-transplant aHUS.
CONCLUSION
Calcineurin inhibitors, rejection, DSA, infections, surgery, and ischemia-reperfusion injury are common triggers that could unmask aHUS in solid-organ transplant recipients. Heterozygous deletion in CFHR3-CFHR1 and CFI VUCS may be important susceptibility factors acting as the first hit for alternative complement pathway dysregulation.
Topics: Humans; Atypical Hemolytic Uremic Syndrome; Mutation; Tacrolimus; Thrombotic Microangiopathies; Kidney Transplantation; Antilymphocyte Serum
PubMed: 37288831
DOI: 10.5414/CN111160 -
Transplantation Oct 2020
Topics: Antilymphocyte Serum; Immunosuppression Therapy; Intestines; Rituximab
PubMed: 31978039
DOI: 10.1097/TP.0000000000003081 -
Annals of Medicine 2023The selection and timing of anti-thymocyte globulin (ATG)-based immunosuppressive therapy (IST) or allogeneic hematopoietic stem cell transplantation (allo-HSCT) in...
Comparison of anti-thymocyte globulin-based immunosuppressive therapy and allogeneic hematopoietic stem cell transplantation in patients with transfusion-dependent non-severe aplastic anaemia: a retrospective study from a single centre.
OBJECTIVES
The selection and timing of anti-thymocyte globulin (ATG)-based immunosuppressive therapy (IST) or allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with transfusion-dependent non-severe aplastic anemia (TD-NSAA) pose significant clinical challenges. This study aims to compare the efficacy and long-term outcomes of the two treatments in TD-NSAA.
METHODS
Patients who underwent ATG-based IST or allo-HSCT between July 2011 and December 2019 were reviewed. We gathered their clinical information, treatment response, survival data, and subsequently analysed the associated risk factors.
RESULTS
A total of 97 TD-NSAA patients were reviewed, and 55 patients who underwent either ATG-based IST ( = 27) or allo-HSCT ( = 28) were enrolled. We observed a significant disparity in the 12-month overall response rate (ORR) (48.1% in IST vs 78.6% in HSCT, < 0.05), but not in five-year overall survival (OS) and event-free survival (EFS). Multivariate Cox regression analysis identified the transfusion of ≥78.75 units of red blood cells (RBCs) as the sole independent risk factor for OS (HR: 17.04, = 0.039) in the IST group. For the HSCT group, disease duration (DD) ≥20 months and transfusion of ≥78.75 units of RBCs predicted an adverse EFS. Frontline IST exhibited superior 12-month ORR (68.8% vs 18.2%, = 0.018) and five-year EFS when compared to non-frontline. Patients with a DD ranging from 6 to 20 months displayed a better EFS ( = 0.016) in HSCT group than those in the ATG-based IST group.
CONCLUSIONS
Prior treatment history, disease duration, and serum ferritin levels should be carefully weighed when making the choice between ATG-based IST and allo-HSCT for TD-NSAA.
Topics: Humans; Antilymphocyte Serum; Anemia, Aplastic; Retrospective Studies; Immunosuppression Therapy; Hematopoietic Stem Cell Transplantation; Treatment Outcome; Graft vs Host Disease; Immunosuppressive Agents
PubMed: 37871262
DOI: 10.1080/07853890.2023.2271475 -
International Journal of Hematology Mar 2024The treatment of aplastic anemia (AA) has significantly advanced in the last 50 years, evolving from a fatal condition to one where survival rates now exceed 80-85%.... (Review)
Review
The treatment of aplastic anemia (AA) has significantly advanced in the last 50 years, evolving from a fatal condition to one where survival rates now exceed 80-85%. Hematopoietic stem cell transplantation (HSCT) and immunosuppressive therapy (IST) have become the primary treatments, with the latter widely adopted due to factors like the scarcity of compatible donors, patient age, comorbidities, and limited HSCT access. A therapy breakthrough was the introduction of antithymocyte globulin (ATG), with its effectiveness further boosted by cyclosporine. However, it took years to achieve another major milestone in management. Initially, treatments aimed to intensify immunosuppression following the success of the ATG-cyclosporine combination, but these methods fell short of expectations. A major turning point was combining immunosuppression with stem cell stimulation, surpassing the efficacy of IST alone. Earlier, growth factors had shown limited success in AA treatment, but thrombopoietin receptor agonists represented a significant advancement. Initially applied alone as salvage, these were later combined with IST, forming the most effective current regimen for medically managing SAA. Horse ATG is the preferred formulation combined with cyclosporine and eltrombopag. This progress in AA treatment offers improved outcomes for patients afflicted with this once-lethal disease.
Topics: Humans; Immunosuppressive Agents; Anemia, Aplastic; Cyclosporine; Antilymphocyte Serum; Immunosuppression Therapy; Treatment Outcome
PubMed: 38403842
DOI: 10.1007/s12185-024-03713-3